Different niches for mutant stem cells affect pathogenesis and therapy response in myeloproliferative neoplasms

Abstract Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis (CH)-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it remains unclear whether distinct bone marrow (BM) HSC niches can influence the growth and therapy response of HSCs carrying the same pathogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera (PV), and endosteal niche expansion in essential thrombocythemia (ET). MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same CH oncogenic driver.